Download Metabolism

The Physiological Mechanisms
Controlling Macronutrient Use During
Exercise
Dr. Randy W. Bryner
Associate Professor and Vice Chair
Director for Undergraduate Education
Division of Exercise Physiology
West Virginia University
Outline
•
•
•
•
Review of specific energy terms
Review of the importance of ATP
General overview of the energy systems
Glycogenolysis and Glycolysis: Factors
which control each
• Mitochondrial metabolism of glucose:
Effects of exercise training
• Use of lipids for energy: Regulatory
processes
Metabolism
• Bioenergetics is the subject of a field of
biochemistry that concerns energy flow through
living systems.
– This is an active area of biological research that includes
the study of thousands of different cellular processes such
as cellular respiration and the many other metabolic
processes within the body.
• Metabolism is the sum of all the chemical reactions
that take place in a living organism.
Metabolism
• Thermodynamics: is a branch of physics concerned with heat
and temperature and their relation to energy and work.
• Important concepts:
• 1. All chemical reactions involve energy changes.
• 2. Chemical reactions in living organisms are catalyzed by
enzymes.
• 3. Enzymes attempt to drive the reaction they catalyze
toward equilibrium.
• 4. As enzyme-catalyzed reactions proceed toward
equilibrium, they release energy.
• 5. The farther a reaction is from equilibrium, the more
energy it can release.
• 6. Some energy released in a chemical reaction can be used to
do useful work; the remainder is unavailable
Energy Change
• Energy is not created or destroyed; it is
acquired in one form and converted to
another.
• The conversion process is fairly
inefficient; much of the energy released is
in a nonusable form: heat
Free energy change: (ΔG)
• That part of the total energy change in a reaction
or process that is capable of doing work at
constant temperature and pressure.
• When free energy is released (considered
negative) the reaction is said to be exergonic.
• When energy must be added to the reaction
(considered positive) the reaction is said to be
endergonic.
Second Law of Thermodynamics
• The second law of thermodynamics states
that entropy is always increasing in the
universe. When a reaction has reached the
end of the road and entropy is at maximum,
the reaction has reached equilibrium. (no
further potential to do work)
Adenosine Triphosphate (ATP): The
Common Chemical Intermediate
ATP is the common chemical intermediate used
to power muscle contractions and other
forms of cell work.
Cells, tissues, and organs are designed to
maintain constant cellular ATP
concentrations.
Adenosine Triphosphate (ATP): The
Common Chemical Intermediate
• ATP acts within the cell as both an energy receiver
and as an energy donor.
– Content in fast skeletal muscle is 7 to 8 μmol/g
– Utilization: Rest = 0.01 μmol . g-1 . s-1
– Maximal tetanic contraction = 10 μmol . g-1 . s-1
–
The estimated ATP cost of maximum voluntary contractions in human muscle ranges from 0.5 to 2 μmol .
g-1 . s-1
•
ATP depletion rarely occurs within the muscle.
–
(Depletion rate rarely exceeds 30-40% even during the most intense exercise)
Creatine Phosphate
• Much more cellular energy is stored in the
form of creatine phosphate (CP) than in the
form of ATP. The metabolism of ATP and CP
are linked by the reaction governed by the
enzyme creatine kinase.
• ADP + CP Creatine → ATP + C
kinase
(Total capacity in fast muscle is approximately 25-30 μmol/g)
•
ATP is replenished almost immediately by CP
ATP
• The reaction in which ATP is split to ADP to liberate
energy involve water. These reactions are called
hydrolyses, meaning "split by water."
• ATP + H2O ATPase
•
→ ADP + P
1
(Standard free energy of ATP hydrolyses is -7.3 kcal/mol. Because pH can affect the free
energy of hydrolyses the value is probably closer to -11 kcal/mol in the working muscle)
ATP
• Three factors operate to give ATP a relatively high
free energy of hydrolysis:
• 1. The negative charges of the phosphates repel
each other.
• 2. The products ADP and P form "resonance
hybrids," which means that they can share electrons
in ways to reduce the energy state.
• 3. ADP and ATP have the proper configurations to
be accepted by enzymes that regulate energyyielding and energy-requiring reactions.
Exercise Metabolism
• The rate of ATP hydrolysis depends on:
– a. Fiber type (ie. Myosin ATPase isoform)
• fused isometric tetanus in cat soleus = 2.4 μmol
ATP . g-1 . s-1 vs cat biceps brachii = 8.0
(The association between elite performance in endurance sports and high percentage of slow fibers
may be largely due to greater economy of slow fibers rather than to differences in mitochondrial
content between human fiber types.)
– b. the peak force and mechanical nature of
the contraction
Exercise Metabolism
• The greater the force the higher the
ATPase activity
• ATPase activity:
– Concentric > Isometric > Eccentric
•
The estimated ATP cost of maximum voluntary
contractions in human muscles ranges from 0.5
to 2.0 μmol . g-1
Skeletal Muscle has There Energy
Systems
• 1. Immediate Energy Source (Power
Events)
• 2. Nonoxidative or Glycolytic (few
seconds to 1 minute)
• 3. Oxidative (two minutes or greater )
Energy Sources of Muscular Work for Different
Types of Activities
Power
Speed
Endurance
Duration of Event
0 to 3 sec
4 to 50 sec
> 2 min
Example of Event
Shot put, discuss,
weight lifting
100 to 400-m run
> 1500-m run
Enzyme system
Single enzyme
One complex
pathway
Several complex
pathways
Enzyme location
Cytosol
Cytosol
Cytosol and
mitochondria
Fuel storage site
Cytosol
Cytosol
Cytosol, blood, liver,
adipose tissue
Rate of process
Immediate, very
rapid
Rapid
Slower but prolonged
Storage form
ATP, creatine
phosphate
Muscle glycogen and
glucose
Muscle and liver
glycogen, glucose;
muscle, blood, and adipose tissue
lipids, blood and liver amino acids
Oxygen involved
No
No
Yes
Immediate
• 1. ATP
• 2. Creatine phosphate (5 to 6 times greater
concentrations then ATP within muscle)
• 3. Adenylate kinase (myokinase)
ADP + ADP Adenylate
→ ATP + AMP
Kinase
•
(All three are water soluble therefore they exist throughout the aqueous part of the
cell. i.e.- cytosol)
Immediate
• Total capacity of the high energy
phosphate system in fast muscle is
approximately 40 μmol . g-1 (In theory: sustain
maximal contractions at 10 µmol .g-1 .s-1 for 4 seconds)
Nonoxidative
• 1. Glycolysis
– Glucose nonoxidative → 2 ATP + 2 lactate
•
rapid glycolysis
•
2. Glycogenolysis
•
In skeletal muscle, the concentration of free glucose is very low, so most of the potential energy available from
nonoxidative energy sources comes from the breakdown of glycogen.
•
*Intense muscular activities lasting longer than approximately 30 seconds cannot be sustained without the benefit of
oxidative metabolism
Glycolytic ATP Synthesis
• The total ATP generation by this pathway
alone is approximately 150 to 300 μmol
ATP . g-1 (enough to sustain maximal contraction for up to 30
seconds)
•
The pathway is efficient; most of potential energy remains in lactate.
Oxidative Energy Sources
• Potential energy sources for muscle
include sugars, carbohydrates, fats, and
amino acids.
– Glucose + Oxygen → 36 ATP + CO2 + H2O
•
The flux through all 3 pathways occur simultaneously.
Maximal Power and Capacity of the Three
Energy Systems
System
Maximal Power
(kcal/min)
Maximal Capacity
(Total kcal Available)
Immediate energy
sources (ATP + CP)
36
11.1
Nonoxidative energy
sources (anaerobic
glycolysis)
16
15.0
Oxidative energy
sources (from muscle
glycogen only)
10
480
Enzymatic Regulation of
Metabolism
• a. Although enzymes cannot change the
equilibria of reactions, they can lower the
energies of activation, thereby allowing
spontaneous reactions to proceed.
• b. By linking exergonic to endergonic
reactions through the use of ATP or other
high-energy intermediates, enzymes facilitate
endergonic processes.
• Different enzymes have different properties that
have great effects on metabolism. Among these
properties is the rate at which the enzyme
functions.
• Maximum velocity (Vmax) is an important descriptive parameter.
•
The Michaelis-Menten constant (Km) is the substrate concentration that gives half of
the Vmax.
Adenylate Energy Charge (AEC)
• AEC = ½ (
»
2[ATP] + [ADP] )
[ATP] + [ADP] + [AMP]
»Is critically important in the regulation of cell metabolism
»In vivo, is regulated to be at 0.8
»AEC tends to fall during muscle contractions
»ADP and AMP are powerful regulators of metabolism
Glycogenolysis and Glycolysis
in the Muscle
• Of the three main foodstuffs, only CHO can be degraded
without the direct participation of oxygen.
• The main product of dietary sugar and starch digestion is
glucose, which is released into the blood of the systemic
circulation.
• Under fasting conditions, glucose concentrations are
maintained by degradation of glycogen in the liver
(glycogenolysis) and production of glucose in the liver
and kidneys from precursors (mainly lactate) delivered in
the circulation
– (the liver stores the greatest concentration of glycogen; skeletal
muscle, because of its overall size, stores the greatest quantity)
Glucose regulation
• The concentration of glucose in plasma is one of the
most precisely regulated physiological variables
(100 mg/dl or 5.5 mM)
• RDA = 130 g/day (520 kcal/day)
• Liver is the main organ of glucose production
– Resting value: 1.8 mg/kg body weight/min
– Exercise of 50% VO2: hepatic glucose production rises to approximately 3.5 mg/kg/min
(even greater values are seen during max exercise)
–
Stores about 50 g/kg tissue/ total ~90-100 g
–
The brain glucose uptake is ~ twice the rate of brain glucose utilization (~ 100 g/day)
Direct vs. Indirect pathways of liver
glycogen synthesis: The "Glucose Paradox"
• Adequate dietary CHO intake is essential to ensure optimal
CHO availability before, during, and after exercise.
• Blood glucose may also come from indirect sources (i.e.,
lactate).
• Because skeletal muscle is the largest tissue containing
enzymes of glycolysis, much of the glucose-to-lactate
conversion is thought to occur in muscle.
• Approximately 60% of the liver glycogen synthesis is by the
direct pathway, whereas 40% is by the indirect pathway
• Indicates the importance of lactate for the maintenance of blood
glucose
Glycolysis
• The metabolic pathways of glucose breakdown in
mammalian cells (the dissolution of sugar)
• The pathway is sometimes called "anaerobic," because
oxygen is not directly involved
• This process is very active in skeletal muscle (often
termed a glycolytic tissue) - pale or white skeletal muscle
has large quantities of glycolytic enzymes
•
Two forms of glycolysis:
• a. “aerobic”
• b. “anaerobic”
Anaerobic
(fast)
glycolysis
Aerobic (slow)
glycolysis
Glucose
Glucose
-47 kcal
2 Lactate
2 Lactate
-686 kcal
2 Pyruvate
-639 kcal
6 CO2 + 6
H2O
Nicotinamide Adenine
Dinucleotide:
• Nicotinamide is a product of B vitamin
• Coenzyme that transfers hydrogen ions and
electrons within cells.
• Hydrogen atoms are frequently removed from
nutrient substrates in bioenergetic pathways
(along with their high energy electrons)
• The Hydrogen atoms must be continuously
picked up by the carrier molecules in order for
glycolysis to continue.
•
(Chicken, turkey, salmon and other fish including canned tuna packed in water are all
excellent natural sources of niacin. Fortified cereals, legumes, peanuts, pasta and whole
wheat also supply varying amounts)
Flavin Adenine Dinucleotide:
• Can be reduced to FADH2 and like NADH, functions
to conserve and transport reducing equivalents.
•
NADH generates 3 ATP molecules within the mitochondria for each
atom of O2.
•
FADH2 generates 2 ATP molecules within the mitochondria.
•
(Milk and milk products such as yogurt and cheese are rich in riboflavin. Asparagus, spinach and other dark green leafy vegetables,
chicken, fish, eggs and fortified cereals also supply significant amounts of riboflavin )
• The net formation of lactate or pyruvate depends on
relative glycolytic and mitochondrial activities, and
not on the presence of oxygen.
•
• Glycolytic flux in excess of mitochondrial demand
results in lactate production simple because LDH has
the highest Vmax of any glycolytic enzyme and because the Keq and ΔG of
pyruvate-to-lactate conversion favors product formation.
Cytoplasmic-Mitochondrial
Shuttle System
• A. Malate-aspartate shuttle (predominates in the
heart)
– This shuttle system uses NADH reduction in cytosol and
NADH oxidation in the mitochondria. (Therefore get 3 ATPs
per NADH)
• B. Glycerol-phosphate shuttle (predominates in
the skeletal muscle)
– The glycerol-phosphate shuttle transfers electrons on cytosolic
NADH to FAD within the mitochondria. (Therefore get 2
ATPs per NADH)
Cytoplasmic-Mitochondrial
Shuttle System (cont.)
• C. Intracellular lactate shuttle permits
both reducing equivalents as well as
oxidizable substrate (lactate) to gain entry
into mitochondria.
– Lactate shuttle operates when glycolysis is
rapid and lactate accumulates.
The Efficiency of Glycolysis:
• Skeletal muscle (white and red glycolytic fibers)
can break down glucose rapidly and can produce
significant quantities of ATP for short periods
during glycolysis.
• * The efficiency of glycolysis is excellent.
• The energy change from glucose to lactate is -47
kcal/mol
The Efficiency of Glycolysis:
(cont.)
• If two ATPs are formed and ∆G0' for ATP = -7.3 kcal/mol
•
Efficiency = 2(-7.3) = 31%
»
•
-47
If ∆G for ATP is -11 kcal/mole
•
Efficiency = 2(-11) = 46.8%
»
-47
The Control of Glycolysis:
• A. Feed-forward controls (Are factors that
increase glucose-phosphate levels which tends to
stimulate glycolysis)
• 1) Stimulation of glycolysis (By epinephrine and
contractions)
• 2) Increase glucose uptake (contractions and
insulin)
The Control of Glycolysis:
(cont.)
• B. Feed-back controls (Involve changes in levels
of metabolites that:
• 1. Result from glycolysis (ie., citrate)
• 2. Result from contraction (ie., ADP)
• 3. Result from a decrease in blood glucose (as
often occurs post exercise) * Is probably the most
important control in normal, healthy subjects.
Enhanced Glucose Uptake
• Rest to exercise glucose uptake can
increase significantly:
– Increased blood flow
– Increased glucose extraction
GLUT-4 and Glucose Transporter
Translocation
• Recent advances indicate that glucose uptake into muscle
and other cells occurs via glucose transport proteins.
• Both muscle and adipose tissue contain both:
– non-insulin (GLUT-1)
– insulin-mediated (GLUT-4) glucose uptake
transporters
• When glucose and insulin levels are high or during
exercise: most glucose enters muscle cells by the insulin
(and contraction) regulatable (GLUT-4) proteins
• GLUT-4 proteins may be are located near T-tubules of the
sarcoplasmic reticulum.
Aerobic Training
• Reduced glucose uptake during
submaximal exercise (absolute load)
• Greater glucose uptake at maximal load
– Enhanced GLUT4 proteins
Phosphofructokinase (PFK):
• Exists in two forms:
– 1. PFK-1 (predominates in muscle; used for
glycolysis)
– 2. PFK-2 (used for gluconeogenesis)
• PFK is a multivalent, allosteric enzyme, which
means several metabolites bind to the enzyme
and affect its catalytic capacity
• May be the rate-limiting enzyme of glycolysis.
Phosphofructokinase
• Stimulators:
– ADP, AMP, Pi, increased pH
• Inhibitors:
– ATP, CP, citrate
Lactic Dehydrogenase (LDH)
• Is the terminal enzyme of glycolysis causing the
formation of lactic acid from pyruvic acid
• There is a significant quantity of this enzyme in muscle
(e.g. white muscle)
• The Keq (equilibrium constant) is large and the reaction proceeds actively to completion
•
Two types of LDH: (Which differ for their affinities for reactants and products)
–
1. muscle (M) - high affinity for pyruvate
–
2. heart (H) - low affinity for pyruvate
Lactic Dehydrogenase (LDH)
• New data has shown that LDH also exist
within the mitochondria
• Each LDH also has four subunits therefore
making five possible arrangements: M4, M3H1,
etc. called isozymes
•
White skeletal muscle has large quantities of LDH and a preponderance of
M4, resulting in lactate production regardless of the presence of O2.
Pyruvate Dehydrogenase:
• A mitochondrial enzyme which can affect
the rate of lactate production.
• When active, causes pyruvate to be
diverted to the mitochondria, also
indirectly affects the NADH/NAD ratio.
Cytoplasmic Redox:
• The NADH/NAD+ ratio (or Redox) affects the activity of
glyceraldehyde 3-phosphate dehydrogenase, which requires NADH as a
co-factor.
•
In general: Cytoplasmic reduction (increased NADH/NAD+) slows
glycolysis; oxidation would speed glycolysis.
Glycogenolysis:
• Skeletal muscle is heavily dependent on
intramuscular glycogen.
• 80% or more of the carbon for glycolysis in
muscle comes from glycogen.
• The utilization of muscle glycogen is most
rapid at the onset of exercise and increases
exponentially with increasing intensity.
Glycogenolysis:
• The rate of use can vary from 1-2 mmol . kg-1 .
min-1 (prolonged submaximal exercise) to 40 mmol . kg-1 . min-1 (very
intense exercise)
•
Factors that influence the rate of muscle glycogen use include exercise
intensity, duration, preceding diet, and training status.
Glycogenolysis:
• Glycogen formation is dependent on glycogen
synthase
• Glycogen breakdown is controlled by phosphorylase
which is controlled by two mechanisms:
• Hormonal mediation - (Slow mechanism)
–
extracelluar: epinephrine
–
intracelluar: cAMP
• Important for two purposes:
– a. Amplifies the local Calcium mediated process in
active muscle
– b. Mobilizes glycogen in inactive tissues to provide
lactate as a fuel and a gluconeogenic precursor
Glycogenolysis: (cont.)
• Mediated by intracelluar Ca2+ released from the SR.
• Also mediated by the inorganic phosphate level of the cell ( a substrate for
phosphorylase) and AMP and ADP.
•
*Probably the most important mechanism during exercise
The Lactate Shuttle
• Recent results have indicated that lactate is
actively oxidized in working muscle beds and
may be a preferred fuel in heart and red skeletal
muscle.
• Skeletal muscle tissue is both the major site of
lactate production as well as utilization.
• Much of the lactate produced in a working
muscle is consumed within the same tissue and
never reaches the blood.
Summary of Lactic Acid
• Can be used for energy by the muscle cell
in which it is produced.
• Can be used for energy by a neighboring
muscle cell (e.g. fast twitch to slow twitch
shuttle)
• Can be used by the liver as a
gluconeogenic precursor.
Gluconeogenesis
• Because glycolysis is an exergonic
process, gluconeogenesis must be
endergonic
• This process is under endocrine control
and occurs primarily in the liver not the
skeletal muscle.
Effects of Training on Glycolysis:
• Endurance training appears to have relatively insignificant
effects on catalytic activities of glycolytic enzymes.
• At present, endurance training has no significant effect on
PFK.
• Endurance training has been observed to decrease LDH
activity in fast glycolytic muscle and to influence the LDH
isozymes in muscle to include more of the heart type.
• Endurance training decreases blood lactate concentration.
• This effect is due to an improved lactate clearance after
training.
Mitochondria
• Cellular oxidation takes place in cellular organelles called
mitochondria.
• The mitochondria appear to be located in two primary
locations:
– a. subsarcolemmal - immediately beneath the
sarcolemma
• - are located at a good position to accept O2 from the
arterial circulation
•
- provide the energy to maintain sarcolemma (ie., E requiring exchange of ions and
metabolites across membrane)
Mitochondria (cont.)
• b. intermyofibrillar - exist among the contractile
elements of the muscle (deep within the cell)
– appear to have a higher activity per unit mass
– probably play a major role in maintaining the ATP
supply for energy transduction during contraction.
• Red-pigmented muscle fibers obtain their color,
in part, from their number of mitochondria,
which are red.
• Pale muscle fibers contain few mitochondria.
Krebs Cycle
• Pyruvate gains entry into the mitochondrial matrix via
carrier proteins located on the outer mitochondrial
membrane (carrier may also transport lactate).
• Also called the citric acid cycle or tricarboxylic acid
cycle (initial constituents have three carboxyl groups).
• Pyruvate is initially catalyzed by pyruvate dehydrogenase
(PDH)
• Purposes of PDH and TCA cycle:
– Decarboxylation (CO2 formation)
– ATP production
– NADH production
Pyruvate Dehydrogenase:
• This is an enzyme controlled by the
phosphorylation state:
• A. When phosphorylated by a specific kinase
that uses ATP, PDH is inhibited.
– Caused by: high ATP/ADP, acetyl-CoA/CoA,
NADH/NAD
• *Acts to reduce glycolytic flux to the
TCA
Pyruvate Dehydrogenase: (cont.)
• B. When dephosphorylated by a specific
phosphatase, PDH is activated.
– Caused by: high levels of pyruvate and Calcium,
decreases in ATP/ADP, acetyl-CoA/CoA, and
NADH/NAD
• Also, insulin binding to the cell surface results in
dephosphorylation of PDH
• *Is a rate-limiting enzyme:
• Helps determine the rates of glycolysis lactate
production and CHO supply for mitochondrial
oxidation
Electron Transport Chain:
• Located on the mitochondrial inner membrane.
• Oxidative Phosphorylation refers to two separate
processes that usually function together.
Oxidation is a spontaneous process that is linked
or coupled to the phosphorylation, the union of
Pi with ADP to make ATP.
Review total number of ATP molecules from
glucose
• Remember, hexokinase is the enzyme required for a
molecule of glucose to enter the glycolytic pathway
(Which also requires one ATP molecule)
• Phosphorylase is the enzyme catalyzing
glycogenolysis. In starting glycolysis from glucose,
each molecule has to be phosphorylated. In
glycogenolysis, the enzyme rather than the substrate
is phosphorylated.
Review continued
• The activity of phosphorylase is much higher in
muscle than is the activity of hexokinase.
Consequently, entry of glucosyl units into glycolysis
during exercise is more rapid from glycogen than
from glucose.
• The ATP for anaerobic glycolysis during heavy
exercise reflects the dominant role of glycogenolysis
and is closer to 3 then 2.
Effects of training on skeletal
muscle mitochondria:
• A number of studies have reported that in
response to endurance-training, several enzymes
of the TCA cycle and constituents of the ETC
have been observed to double in activity.
• Is there an increase in the number or density of
enzymes on the mitochondria cristae or is there
simply more mitochondria?
• Answer: Enzymatic activity per unit
mitochondrial protein does not increase. Rather,
there are more mitochondria or there is a more
elaborate reticulum.
Effects of training on skeletal
muscle mitochondria:
• Significance:
• Appears to be related more to endurance time as
compared with max VO2.
– The reason for this is not really known but may be that increased
mitochondrial mass increases the sensitivity of respiratory control.
• Allows a given rate of mitochondrial oxygen to be
accomplished at a higher ATP/ADP ratio.
– This increased sensitivity of respiratory control is thought to down
regulate glycolysis, thus allowing for greater lipid oxidation at a
given oxygen consumption.
• It may be that training has a greater effect on
subsarcolemmal mitochondria,
– This would improve the ability to maintain the integrity of the cell
membrane and thus improve endurance during heavy exercise.
Effects of training on skeletal
muscle mitochondria:
• Calcium ions and ATP turnover appear to be
most responsible for the mitochondrial
biogenesis following exercise.
• These, along with other signaling molecules
appear to activate kinases (i.e., protein kinase
C, AMP-active protein kinase) which can
ultimately influence the expression of
nuclear genes encoding for mitochondrial
proteins.
Lipid Metabolism
• A lipid is a substance that is soluble in organic
solvents but not water.
• Fatty acids (ie., stearate) are long chain
carboxylic acids (contain a carboxyl group) Usually contain an even number (14 to 24) of
carbons in a straight chain.
• Esterification - The process of making
triglycerides; involves attachment of a fatty acid
to glycerol by means of an oxygen atom.
• Lipolysis - The process of triglyceride
dissolution
Lipid Metabolism
• Mobilization - the breakdown of adipose and
intramuscular triglyceride
– a. adipose capillary wall lipoprotein lipase (LPL)
• stimulated by insulin and high blood glucose levels to
promote fat storage.
– b. hormone sensitive lipase (HSL)
• stimulates fat breakdown, is inhibited by insulin, and is
stimulated by other hormones such as the catecholamines
(fast acting) and growth hormone (slow acting)
• directly controlled by the presence of cyclic AMP which is
regulated by the adenylate cyclase system.
Adipose Tissue Lipolysis
• Lipolysis, in part, depends on the activation
(phosphorylation by PKA) of HSL.
• However, studies using HSL-null mice
showed some DG accumulation and βadrenergic stimulated lipolysis.
• Adipose triglyceride lipase (ATGL) also
involved and is believed to initiate lipolysis
(TG
DG)
• HSL then hydrolyzes DG to FFA and MG
• MG lipase form FFA and glycerol
Adipose Tissue Lipolysis
• ATGL mediates basal and β-adrenergic
TG lipolysis (deletion induces obesity and
over-expression produces a lean
phenotype)
• Activated ATGL and HSL move to the
vicinity of the lipid droplets and interact
with the regulatory protein perilipin A
(normally encase the lipid droplet/ protect
from degradation)
Physiological Regulation of Resting
Lipolysis
• Low concentrations of EPI and NE result in
inhibition of lipolysis. (through activation of α2-2
receptors which ultimately decrease cAMP)
•
Adenosine binds to adenosine receptors and inhibits lipolysis (caffeine antagonizes this
affect)
•
Blood insulin is the major inhibitor of lipolysis at rest.
–
1. Direct inhibition of adenylate cyclase (AC) activity
–
2. Activation of phosphodiesterase activity (reduces cAMP)
–
3. Direct inhibition of PKA, reducing activation of HSL
–
4.
Activation of phosphatase, which deactivates HSL
Physiologic Regulation of Lipolysis
during Exercise
• Sympathetic NS outflow results in an
increased blood level of EPI and NE.
• Increased concentrations of these
catecholamines results in a stimulation of
lipolysis (through activation of β1 receptors)
•
Escape of FFA into blood depends on membrane fat transport proteins and
albumin.
Lipid Metabolism
• Circulation - the transport of free fatty acids (FFAs)
from adipose to muscle.
– Increased FFA levels occur during mild to
moderate intensity exercises of 65% VO2max or less.
–
During prolonged low to moderate intensity exercise, blood FFA increases within 10
to 30 minutes
Lipid Metabolism
• Uptake - the entry of FFAs into muscles from
blood (Fatty Acid Binding Proteins)
– It has been demonstrated that as many as half of
the arterial FFAs are removed from the muscle
capillary bed during each circulation of blood
through the muscle.
– Therefore, any factor that stimulates adipose
lipolysis and raises blood FFA levels could
promote exercise endurance.
Lipid Uptake
• Dependent on arterial fatty acid content (e.g.,
anything that increases adipose tissue lipolysis will
increase FFA levels)
• Dependent on tissue blood flow (red vs. white
skeletal muscle, enhanced CO and blood delivery
due to endurance training).
• Depended on the number of sarcolemmal fatty acid
binding proteins and fatty acid transporter.
– FABPPM – located on the outer plasma membrane
–
FATPs (FATP 1,4) – family of transmembrane proteins
–
FAT/CD36 – has two transmembrane domains
FFA Transport Across Muscle Membrane
• FAT/CD36 protein was recently shown to acutely
translocate from an intracellular pool to the plasma
membrane during a single bout of exercise. (similar
to GLUT 4)
• Other FA transport proteins may do the same.
• Heart muscles cells number > then red skeletal
number > then white skeletal number.
• Endurance training significantly increases number
• The time course for FFA uptake and oxidation
appears to be slower than that for glucose uptake,
glycogen breakdown and CHO metabolism during
exercise.
Lipid Metabolism
• Activation - raising the energy level of fatty
acids preparatory to catabolism
• Translocation - the entry of activated fatty
acids into mitochondria
• β Oxidation - the catabolism of acetyl-CoA
of activated fatty acids and the production of
reducing equivalents (NADH and FADH)
• Mitochondrial oxidation - Krebs cycle and
electron transport chain activity.
Activation and Translocation
• Fatty acid is activated by use of an ATP
and is attached to coenzyme A forming
fatty acyl-CoA (occurs in the cytosol or on
outer mitochondrial membrane).
• Must be shuttled into the mitochondrial
matrix.
• This process is catalyzed by a family of
enzymes collectively called Carnitine
Acyl transferase 1 (CAT)
Translocation
• Carnitine Acyl transferase 1 (CAT) is
inhibited by malonyl-Co A an intermediate in
fatty acid synthesis
• (pyruvate formation from glycolysis also
leads to formation)
• Malonyl-CoA has been shown to decrease
during exercise in rat skeletal muscle
– Decline may not be enough to allow for significant increases in fat
oxidation in the working muscle. May be more important in the nonworking muscle.
Carnitine Palmitoyltransferase Complex
• Complex which consists of CPT1,
acylcarnitine translocase, CPT II
• Plays an important role regulating the
transport of long chain fatty acids into the
mitochondria.
• CPT1 has been shown to be inhibited by
small, physiologically relevant decreases
in pH (7.0 to 6.8)
β - Oxidation
• β – Oxidation may be affected by the
redox ratio (e.g., high NADH/NAD
inhibits dehydrogenase enzymes only
because of a lack of NAD)
• However, it appears that the primary
regulator is the availability of pathway
substrates (fatty acyl-CoA, H2O, NAD+, FAD, and
free CoA)
• Beta oxidation cont.
– For an 18 carbon fatty acid:
– 18 carbons
= 9 Acetyl units
– Cycles through Beta oxidation = 8 Cycles
– Each 8 Cycles  1FADH2
(8 X 2
=16ATP)
– Each 8 Cycles  1 NADH
(8 X 3
=24ATP)
– Each of 9 Acetyl-CoA enter Krebs cycle  12ATP/Acetyl-CoA. (12 X 9 = 108
ATP).
– 16 + 24 + 108 = 148 ATP - 1ATP for activation = 147 ATP
• Beta oxidation cont.
– Because there are 3 fatty acid molecules for
each triglyceride molecule, 147 X 3 =
441ATP.
– 441 ATP plus 19 ATP from glycerol
catabolism = 460 ATP Total.
Intramuscular Triglycerides and
Lipoprotein as Fuel Sources
• a. lipoprotein lipase (LPL)- within muscle capillary
wall hydrolyzes triglycerides in blood lipoproteins and
makes the resulting FA available in muscle.
• b. lipoprotein lipase (ATGL, L-HSL, MGL)- exist
within muscle cell; hydrolyses triglycerides in circulating
lipoproteins as well as the triglyceride stores within
muscle cells.
– inhibited by high insulin levels and stimulated by high
levels of glucagon and growth hormone.
– endurance training can increase L-HSL
Intramuscular Triglycerides and
Lipoprotein as Fuel Sources
• The muscle stores a significant amount of fat.
• The range is approximately 20 to 40 mmol/kg dry
muscle
• This is equivalent to approximately 60-100% of the
energy stored as glycogen
• HSL is found in high quantities in skeletal muscle
• Under the influence of Epi, Ca2+, and insulin
• Other “intracellular” mechanisms also involved
Mitochondrial Adaptation to
Enhance Fat Oxidation
• Why does mitochondrial mass increase 100% after
aerobic training but maximal cardiac output increase only
10-20%?
• Answer: In part, to increase the use of fats.
• Muscles of trained individuals can increase ATP
production via fat utilization which can inhibit PFK and
PDH (slows glycolysis and catabolism of glucose and
glycogen).
• Mitochondrial proliferation can raise the Vmax of fat oxidation.
(Thus, in trained individuals, the absolute utilization of fat is greater at any given FFA
concentration)
Importance of Lipids during Exercise
• Small uptake of FFA by muscle during exercise
(training can significantly increase this value)
• Some studies have reported that Intramuscular
triglycerides are not significantly mobilized during
most activities except when glycogen becomes
depleted.
• However, recent evidence indicates that IMTG is an
important substrate during prolonged moderateintensity dynamic exercise ( ~50%-65% VO2max) and
possibly up to 85% VO2max in well-trained athletes.
•
Intramuscular triglycerides are used during recovery from fatiguing exercise.
Classic Carbohydrate-Fatty Acid
Interaction Studies
• Fuel Selection in Cardiac and Diaphragm Muscles
• The early work by Randle and others establishing the
G-FA cycle were done in cardiac and diaphragm
muscles which get most of their energy from
exogenous substrates.
– Glucose fatty acid (G-FA) cycle
• Reciprocal relation between fat & carbohydrate (CHO) oxidation
• Increasing availability of fat FA while CHO oxidation
• In exercising muscle (~80 VO2max) for which fat supply was
artificially increased, glycogen use was shown to be decreased by ~ 50%.
Glucose-Fatty Acid Interactions during
Exercise
Classic Carbohydrate-Fatty Acid
Interaction Studies (cont’d)
• Fuel Selection in Resting and Contracting
Muscles
– Original G-FA cycle applied to diaphragm & cardiac muscles
– Skeletal muscle, however:
• Has much larger variations in metabolic demands
• Draws CHO & lipid from different sources: circulation & muscle
– Mechanisms in G-FA cycle may not apply to skeletal muscles
Increased Lipid Availability During
Dynamic Exercise in Humans
• Effects of Increased Plasma FFA on CHO Metabolism in
Human Skeletal Muscle
– Original G-FA cycle did not account for regulation of glycogen PHOS
– Altering substrate availability:
• Changes intracellular environment of skeletal muscle
• Creates reciprocal relationship between CHO & FA oxidation
– These shifts in fuel selection involve changes in activation of:
• PHOS
• PFK
• PDH
CHO-FFA Interactions in Exercising Skeletal
Muscle
• It appeared that the fat-induced down-regulation of
CHO oxidation was at the glycogen phosphorlase
(increased fat availability produced decreases in free
ADP and AMP)
• Increasing fat availability may also increase the
amount/activity of PDK the enzyme responsible for
inhibiting PHD.
• Increasing IMTG, through high fat diets, has been
shown to down regulate glycogen use, but not
glucose uptake during exercise.
Regulation of Key Enzymes in
CHO Metabolism
Potential Intracellular Signals That Regulate
Fuel Preference During Exercise
• Decreased glycogenolysis with high fat
provision may be explained by reductions
in:
– ADP
– AMP
– Pi
Reciprocal Relationship Between CHO and Fat
Oxidation During Exercise
Increased FFA Availability During
Prolonged Dynamic Exercise
• With moderate exercise prolonged beyond 1 to 2 hours:
Availability of plasma FFA
Availability of muscle glycogen
Fat oxidation
CHO oxidation
PDHa
– No change in energy status of cell
– No decreases in pyruvate content
• High fat availability:
– Upregulates PDK activity
PDH activity
Crossover Concept
• The power output is the most important factor in
determining the fuels used during exercise (other
factors such as diet, training, gender and age are
secondary).
• At rest: ~60% fat, ~35% CHO, ~5% protein
• Contraction leads to an increase in intracellular Ca++
and P
•
•
•
•
i which activates phosphorylase.
Increased blood lactic acid inhibits lipolysis.
Increased pyruvate increases malonyl-CoA formation which inhibits CPT1 and
mitochondrial FFA uptake (May not be important during exercise).
Increased acetyl-CoA from pyruvate inhibits β-ketothiolase, the terminal enzyme in βoxidation.
Training shifts the crossover point to higher absolute and relative power outputs.
Fat Use at Higher Intensities
• Decreased fat use may be the result of:
– 1. Decreased blood flow to adipose tissue
– 2. Decreased release of FFA into plasma and
reduced delivery to skeletal muscle
– 3. Decreased hydrolysis of IMTG
– 4. Decreased delivery of FFA to skeletal
muscle mitochondria
– 5. Decreased pH reducing FFA transport into
mitochondria
Increased Carbohydrate
Availability and Dynamic Exercise
• Increased Exogenous Glucose Availability
– Inhibits fat utilization during exercise due to combined effects of:
FFA availability, as a result of
Adipose lipolysis
• Direct effects on FA oxidation in the muscle, all secondary to
Insulin concentration
Potential Effects of CHO Ingestion
Prior to Exercise
AMP-Activated Protein Kinase
• Is AMPK the metabolic master switch in the skeletal muscle?
• Is an enzyme which controls systemic energy expenditure,
glucose homeostasis, lipid metabolism, and mitochondrial
biogenesis
• AMP binds to the α-subunit of AMPK increasing its activity.
• Activated AMPK inactivates acetyl-CoA carboxylase, the
enzyme that produces malonyl-CoA and activates malonyl-CoA
decarboxylase (the enzyme that converts malonyl-CoA to
acetyl-CoA.
• Malonyl-CoA inhibits CPT1 which is the important enzyme for
the transport of activated fatty acyl-CoA across the inner
mitochondrial membrane for β-oxidation.
The Physiology of the
Neuroendocrine System: The
Overall Control of Metabolic
Processes during Exercise
Neural-Endocrine Control of
Metabolism
• The coordinated physiological response to
maintain blood glucose homeostasis during
exercise is governed by two related body
systems:
– a. the autonomic nervous system (primarily
the sympathetic nervous system)
– b. the endocrine system
• When blood glucose falls during prolonged hard
exercise, powerful counterregulatory feedback
controls come into play to increase glucose
production and maintain circulating glucose.
Neural-Endocrine Control of
Metabolism (cont.)
• However, during moderate or greater intensity
exercise, the liver is under "feed-forward"
(neural or hormonally mediated) control to
maintain or raise blood glucose concentrations.
• Feed-forward mechanisms cause arterial glucose
concentration to rise at the start of moderate and
greater intensity exercises.
Hormones
• Hormones are chemical substances that are
secreted into body fluids, usually by endocrine
glands.
• In the resting person, metabolism is largely
controlled by hormones. During exercise, both
hormonal and intracellular factors control
metabolism.
• Hormones which act specifically to maintain
blood glucose levels are said to be
glucoregulatory.
Types of Hormones
• Two Chemical Categories of Hormones:
– 1) Steroid-derived hormones: not soluble in blood
plasma; synthesized from circulating cholesterol via
adrenal cortex and gonads; receptors are usually found
within the cell.
– 2) Hormones synthesized from amino acids (amine or
polypeptide hormones): soluble in blood plasma;
receptors are located on the cell membrane of target
tissues.
Target’s Cell Ability to Respond
• Depends on:
– Presence of specific protein receptors that
bind the hormone in a complimentary way
– Target cell receptors occur either:
• On plasma membrane
• In the cell’s interior
Cyclic AMP
• Cyclic AMP:
– Intracellular messenger produced from the binding
hormone (1st messenger) reacting to the enzyme adenylate cyclase (plasma
membrane) forming cyclic 3’5’-adenosine monophosphate (cyclic AMP) from an original
ATP.
–
Cyclic AMP becomes 2nd messenger and activates a specific protein kinase, which then
activates a target enzyme to alter cellular function which is the ultimate goal.
Glycemic Threshold
• The defenses against hypoglycemia are
triggered at “glycemic thresholds.
• Insulin suppressed at ~ 4.5 mM
• Glucagon, GH, and Epinephrine
stimulated at ~ 3.7 mM
• Cortisol stimulated at ~ 3.6 mM
• Cognitive dysfunction occurs at ~ 2.6 mM
Insulin and Glucagon - The
Immediate Control of Blood Glucose
Level:
• Insulin is secreted by the β cells of the pancreatic
islets of Langerhans. (inhibited by α2 – adrenergic sympathetic
stimulation by epinephrine and NE)
•
Plasma glucose concentration is the primary determinant of secretion.
•
Causes glucose uptake by many different cells, of which muscle and adipose is the most
important.
•
A major mechanism of insulin action is facilitating the transport of glucose through cell
membranes by way of a protein carrier. (Translocation Hypothesis)
The mechanism of muscle
contraction
• Induces GLUT-4 translocation through
separate, insulin-independent mechanism
• Calcium may be one of the second
messengers in the translocation of GLUT-4
carriers to the muscle cell surface.
Glucose Transporter 4 (GLUT4)
Cycling in Skeletal Muscle
Effect of Insulin
• Insulin also has a major effect on glucose metabolism by
the liver:
– Stimulates the synthesis of glucokinase which
phosphorylates glucose-6-phosphate (G6P) and causes
the uptake of glucose by the liver and synthesis of
glycogen.
• Once the maximum amount of liver glycogen is stored,
the excess G6P stimulates glycolysis and leads to acetylCoA and fatty acid formation which ultimately lead to
triglyceride formation within the liver.
• Insulin also inhibits hepatic glucose production from
gluconeogenesis.
Insulin
• During exercise, insulin levels decrease significantly most
likely due to epinephrine, which suppresses insulin
secretion.
• Importance:
• a. takes away inhibitory effects of insulin on glucose
production from gluconeogenesis (liver)
• b. minimizes glucose uptake by inactive tissues
• c. with prolonged exercise, glucose and insulin decrease
which enhances lipolysis and FFA availability.
• d. in trained individuals insulin does not fall as far as in
untrained
Insulin
• Red-slow skeletal muscle has more
GLUT-4 and a greater glucose uptake
capacity than white-fast muscle.
Endurance training has also been shown
to increase the amount of GLUT-4 in
human muscle and may cause a greater
number to be located at the cell surface.
Glucagon
• - secreted by the α cells of the pancreas
• - Plasma glucose concentrations is the
primary determinant of secretion.
• Secretion may also be directly (??) or indirectly
controlled by catecholamine because of their
suppressive role on insulin (insulin inhibits
secretion)
Glucagon
• Secretion increases blood glucose by:
• a. enhancing liver glycogenolysis
• b. increasing liver gluconeogenesis
• c. may assist epinephrine effect on
muscle glycogenolysis
• d. promotes liver uptake of AA (i.e.,
alanine)and gluconeogenesis
The Autonomic Nervous System
• Autonomic nervous system is composed
of:
– a. sympathetic NS
– b. parasympathetic NS
• ( controls resting functions through
its release of acetylcholine; ie.,
slowing heart rate and stimulating
digestion)
The Sympathetic Nervous System
• The sympathetic NS controls fight-or-flight responses
through the release of norepinephrine.
• The sympathetic NS stimulates secretion from the
adrenal medulla of catecholamines (epinephrine and
norepinephrine; 4 to 1 ratio of epinephrine to
norepinephrine release by adrenals)
• The circulating level of norepinephrine is approximately
5X that of epinephrine.
• Catecholamines interact with two receptors, alpha and
beta (norepinephrine affects primarily alpha; epinephrine
affects both)
• beta 1 - heart rate
• beta 2 - tissue metabolism
Exercise and Catecholamines
• -Exercise of low to moderate intensity has very
little affect
• -Exercise intensity of 50 to 60% and greater
causes dramatic increases
• -After endurance type training, catecholamine
response to submaximal exercise is diminished
• -However, during hard to maximal intensity
exercise in trained individuals, catecholamine
release is exaggerated over that in untrained
individuals. (Leads to an exaggerated glucose
response)
Catecholamines and Blood Glucose
Homeostasis
• Epinephrine (along with changes in
intramuscular free Ca2+) stimulates muscle glycogenolysis
• - Can also stimulate glycogenolysis in the liver
• As part of the feed-forward mechanism of glycemia regulation, the rapid NE rise
during difficult exercise is thought to support hepatic (liver) glucose production
(HGP), mainly through gluconeogenesis.
Catecholamines and Blood Glucose
Homeostasis (cont.)
• -Epinephrine has an indirect effect by
stimulating hormone-sensitive lipase (ATGL) in
adipose tissue which will raise arterial fatty acid
levels at the start of exercise
• Increased epinephrine levels during exercise
suppresses insulin secretion which ultimately
increases the effects of glucagon by changing the
insulin/glucagon ratio (I/G) even if glucagon
remains constant. (The I/G has profound effects
on HGP)
Rise in Glucose Production During
Moderate Exercise
Hypothalamus/Pituitary Integration:
• -The hypothalamus receives neural inputs
and is sensitive to blood metabolite levels
(e.g., glucose)
• -The hypothalamus synthesizes chemical
factors that either inhibit or stimulate the
synthesis and release of anterior pituitary
hormones (through a series of neurons and
a blood (portal) system.
Growth Hormone
• Growth hormone is a protein molecule released
by the anterior pituitary.
• GH stimulates protein synthesis especially in the
young.
• GH is one of the major lipolytic hormones.
(stimulates fat metabolism and indirectly
suppresses carbohydrate metabolism)
• At present, neural factors (i.e., glucose sensors in
the CNS) are implicated as exerting primary
control over GH secretion during exercise
although the precise mechanism is still
unknown.
Cortisol
• Is a glucocorticoid hormone secreted by the
adrenal cortex.
• Controlled by the HPAC axis
• Stress or low blood glucose levels stimulate the
hypothalamus to secrete corticotropin-releasing
factor which in turn stimulates the anterior
pituitary to release adrenocorticotropin which
causes the release of cortisol
• Stimulates AA release from muscle; stimulates
hepatic gluconeogenesis from AA; helps
mobilize FFAs from adipose tissue.
Cortisol
• May play a secondary role to insulin,
sympathetic activity, and glucagon during
brief periods of hypoglycemia
Cortisol (cont.)
• During prolonged, hard exercise, ACTH is
secreted in response to the level of stress and
to falling blood glucose levels.
– This stimulates cortisol release, which stimulates
proteolysis in muscle and amino acid release into venous
blood or increased alanine synthesis and release.
• During the period of recovery from
exhausting exercise cortisol appears to be
important
– Along with glucagon, cortisol establishes normal blood
glucose levels through the mobilization of muscle proteins
and the stimulation of gluconeogenesis from AA.
Serum Cortisol Concentrations
Glycemic Threshold
• The defenses against hypoglycemia are
triggered at “glycemic thresholds.
– Insulin suppressed at ~ 4.5 mM
– Glucagon, GH, and Epinephrine stimulated at
~ 3.7 mM
– Cortisol stimulated at ~ 3.6 mM
– Cognitive dysfunction occurs at ~ 2.6 mM
• Episodes of hypoglycemia or prolonged
exercise may lower thresholds
Hypoglycemia-associated autonomic
failure (HAAF)
• Insulin-induced hypoglycemia on a day prior to
exercise resulted in a blunting of glucose
counterregulatory hormones, a reduction in glucose
production, a 50% lower rate of lipolysis and an
impaired ability to regulate plasma glucose during
exercise at 50% VO2max
•
Involves a decline in adrenomedullary and SNS activation.
•
The cause of the suppressed sympathetic activity is the stimulation of corticosteroid
receptors in the brain by cortisol. (Does not occur in patients with Addison’s disease;
appears to also be inhibited by estrogen)
Response of Six Hormones to
Exercise
Practical Relevance of (HAAF)
• The neurogenic symptoms to reduced
blood glucose could be reduced in athletes
doing two-a day or heavy daily exercise
training.
Permissive Role of Thyroid Hormones?
• T4 and T3 generally stimulate
metabolism
– increases the rate of processes such as oxygen
consumption, protein synthesis,
glycogenolysis, and lipolysis.
• T3 has the ability to increase cAMP
– Potentiates hormone affects which act through
a cAMP dependent process (permissive role)
Posterior Pituitary Hormones
(neurohypophysis)
•
•
Outgrowth of hypothalamus
Hormones secreted from the Posterior Pituitary are
actually made in the hypothalamus and then secreted
into the posterior pituitary to be stored until needed. (2
specifically)
1.
2.
Antidiuretic hormone (ADH or vasopressin) influences
water excretion by the kidneys by stimulating reabsorption
thus decreasing urine output
Oxytocin initiates muscle contraction in the uterus and
stimulates ejection of milk .
•. Exercise is an important stimulant for ADH
secretion & release.
Antidiuretic Homore
• Two types of stimuli appear to cause
significant release of ADH:
– 1. Plasma osmolality – hypothalamic
supraoptic nuclei are sensitive to changes in
arterial electrolyte concentration.
– 2. Change is arterial BP – initiated via
pressure receptors in the left atrium and other
vascular baroreceptors.
Adrenocortical Hormones
•
Mineralocorticoids are secreted by the adrenal
cortex
-
Regulates the mineral salts such as Na+ and K+ in the extracellular fluid spaces.
-
Controls total Na+ concentration as well as extracellular fluid volume.
-
Regulates sodium reabsorption in the distal tubules of the kidneys.
-
For every Na reabsorbed, K and/or H exchanged which
Aldosterone, most important (95% of all)
helps control proper mineral balance
Aldosterone
• Increases in Aldosterone
– Increases Na reabsorption, little Na fluid
voided in urine
– Increases cardiac output and increases BP
(renin-angiotensin mechanism)
• Decrease in Aldosterone
– Decreases Na reabsorption and decreases
water reabsorption
Aldosterone
• Cellular responses to aldosterone are slow
• It requires relatively prolonged exercise
(>45 min) for aldosterone’s effect to
emerge (usually see affect during
recovery)
Protein Turnover
• Protein is the least oxidized of the three fuels for
meeting energy demands.
• The daily turn over of protein is much higher than
CHO or fats.
– Protein ~ 37 mmol/kg/d
– CHO ~ 15 mmol/kg/d
– Fat ~ 24 mmol/kg/d
• Muscle growth and atrophy are the result of the
small differences in the high rates of synthesis and
breakdown (controlled by separately regulated
processes).
Protein Turnover
• Depends on the intracellular availability of amino
acids.
• Glycogen and glucose depletion reduces the
available pool of amino acids available for protein
synthesis.
• Most proteolysis occurs in a highly selective, tightly
regulated, and therefore controllable process.
Hormone Effects on Protein
Turnover
• Goldberg’s rats:
• Severed insertion of Gastrocnemius
• Compensatory hypertrophy of soleus (~40%) and
plantaris (~20%) muscles (after 5 days)
• Saw similar growth in hypophysectomized,
diabetic and starving rats
• Concluded that mechanism of “work-induced”
hypertrophy was intrinsic to working muscles
(unlike developmental growth which is known to
be affected by circulating pituitary hormones)
• May involve autocrine expression of IGF-1
Hormone Effects on Protein
Turnover
• Wolfe's men:
• Used combination of stable isotope infusion,
arterial and venous blood sampling, and
muscle biopsy to calculate the rates of protein
synthesis and breakdown at one moment in
time.
• Concluded that supplies of nutrients, and the
hormonal responses to those nutrients, determine if
working muscle will grow or atrophy (exercise
magnifies this anabolic response only if glucose and
insulin are available).
Influence of Exercise, Amino
Acids, and Glucose on Mixed
Muscle Protein Turnover
Hormone Effects on Protein
Turnover
• Insulin:
• Suppresses proteolysis (primarily at the skeletal
muscle) independent of blood glucose. (most
consistent finding)
• Only small increases in insulin are necessary to
diminish skeletal muscle protein breakdown.
(effects seen in the lower part of its physiological
range; much lower then is required for glucose
uptake)
• May also enhance protein synthesis (although
hyperinsulinemia has also been shown to suppress
protein synthesis lowering AA availability)
Dose-Response Relationships
Mean Insulin Concentrations and Cortisol-toInsulin Ratios Over Time
Hormone Effects on Protein
Turnover
• Cortisol
• Is known to be catabolic and glucoregulatory
(gluconeogenesis)
• Causes protein breakdown to increase by
increasing the capacity of the ubiquitin-proteosome
system which can accelerate muscle protein
breakdown
• Must have second factor (i.e., Ca2+, low insulin, insulin
resistance, fasting) to fully activate ubiquination
•
Therefore, under nutrition and the energy cost of exercise drive this process by raising
the cortisol-to-insulin ratio.
Mean Insulin Concentrations and Cortisol-toInsulin Ratios Over Time
Cortisol-to-Insulin Ratios during 2
Hours of Exercise in the postabsorptive
state at 70% VO2max
Hormone Effects on Protein
Turnover
• Growth Hormone:
• Peri- and post-puberatal growth depend on a
normal pulsatile secretion.
• May stimulate protein synthesis without
affecting proteolysis
• However, in normal, healthy adults, GH
appears to play only a minor role in promoting
muscle hypertrophy and strength.
• Works through the stimulation of IGF-1
although exercise induced muscle hypertrophy
does not depend on circulating GH or IGF-1
Hormone Effects on Protein Turnover
• IGF-1
• Paracrine/autocrine secetion of IGF-1 has been
shown to occur with muscle exercise and may
be important to the hypertrophy seen under
this condition.
• IGF-1 also reduces glucocorticoid-induced
muscle proteolysis
• IGF-1 may also stimulate the proliferation and
differentiation of satellite cells.
Hormone Effects on Protein Turnover
• Androgens:
• Promotes GH release and therefore IGF (indirect effect).
• Interacts with neural receptors to increase neurotransmitter
release; alters size of neuromuscular junction.
– (Enhances the force-production capabilities of skeletal
muscle)
• In untrained males, both resistance exercise and moderate
aerobic exercise has been shown to increase serum and free
levels after 15 to 20 minutes.
• Values may remain elevated for at least 1-hour post strenuous
exercise
Androgens
• Other data has indicated that a single bout of highvolume resistance exercise can lower total and free
testosterone concentrations by 10% over a 12 hour
period.
• However, regular high-volume resistance exercise
training does not affect basal testosterone
concentrations.
• Resistance training, with anabolic diets and
increased testosterone levels induce substantial
similar and additive gains in FFM, muscle size, and
strength.
Mean Fat-Free Mass, Triceps & Quadriceps
Cross-Sectional Areas, & Muscle Strength
Changes in Fat-Free Mass in Relation to Total
Serum Testosterone Concentrations
• Normal physiological range = 300-1000 ng/dL
Hormone Effects on Protein
Turnover
• Testosterone:
• Acts by increasing muscle protein synthesis
without having any effects on protein breakdown.
• May also increase androgen receptors in skeletal
muscle and satellite cells.
• Electrical stimulation of the muscle and resistance
training also stimulates androgen receptors.
• Testosterone also increases IGF-1 mRNA
bioavailability in muscle.